KR102093660B1 - Temperature-sensitive tissue adhesion prevention hydrogel composition and its manufacturing method - Google Patents
Temperature-sensitive tissue adhesion prevention hydrogel composition and its manufacturing method Download PDFInfo
- Publication number
- KR102093660B1 KR102093660B1 KR1020190107356A KR20190107356A KR102093660B1 KR 102093660 B1 KR102093660 B1 KR 102093660B1 KR 1020190107356 A KR1020190107356 A KR 1020190107356A KR 20190107356 A KR20190107356 A KR 20190107356A KR 102093660 B1 KR102093660 B1 KR 102093660B1
- Authority
- KR
- South Korea
- Prior art keywords
- hydrogel composition
- tissue adhesion
- weight
- hyaluronic acid
- polyethylene oxide
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/042—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/04—Alginic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
- A61L2300/604—Biodegradation
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
본 발명은 조직유착 방지용 하이드로겔 조성물 및 그 제조방법에 관한 것으로, 조직유착 억제성능을 갖는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 기본 구조체로 하고, 수불용성 히알루론산, 소듐알지네이트를 블랜딩하여 체내 상처 부위에 고르게 도포되는 조직유착 방지용 하이드로겔 조성물을 제공하는 조직유착 방지용 하이드로겔 조성물 및 그 제조방법에 관한 것이다.The present invention relates to a hydrogel composition for preventing tissue adhesion and a method for manufacturing the same, based on a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer having tissue adhesion inhibiting performance, and blending water-insoluble hyaluronic acid and sodium alginate The present invention relates to a hydrogel composition for preventing tissue adhesion and a method for manufacturing the same, which provides a hydrogel composition for preventing tissue adhesion, which is evenly applied to a wound in the body.
일반적으로 수술 후 발생하는 장기 및 조직의 유착은 손상된 조직의 세포가 증식하고 재생하는 과정에서 일어나는 자연현상중의 하나이지만, 강하게 조직이 유착되거나 의도하지 않은 다른 조직 및 장기와의 유착은 환자에게 계속되는 불편감이나 기능장애를 일으킨다. 그리고 유착 박리를 위한 재수술이 필요하기도 하며 생명을 위협하는 요인이 되기도 한다. 이러한 조직의 유착은 인체 모든 곳에서 일어나며, 특히 개복 수술 후 70 ~95% 정도의 빈도로 유착이 발생한다. 수술 후에 발생하는 유착의 경우에는 유입된 이물질, 감염에 따른 염증반응, 수술부위의 출혈, 혈액응고, 장막의 파열 등이 원인으로 알려져 있다. 위의 유착원인에서 보다시피 출혈이 유착의 유발에 많은 영향을 끼치지만 체내 온도에 의해 점도가 상승하여 유효성분의 침투와 유착효과를 동시에 나타내는 유착방지제는 아직까지 없는 실정이다. 현재 사용되는 지혈제용 재료는 다당류를 포함한 생체유래 천연고분자, 비생체 유래 천연고분자 등이 있다. 이러한 재료들은 단독으로 또는 특정한 구조를 이루어 함께 사용되고 있는 실정이다.In general, adhesion of organs and tissues that occur after surgery is one of the natural phenomena that occur during the proliferation and regeneration of cells in damaged tissues.However, strongly adhered tissues or unintended adhesions with other tissues and organs continue to the patient. It causes discomfort or dysfunction. In addition, re-surgery for adhesion detachment is necessary and may be a life-threatening factor. Adhesion of these tissues occurs in all parts of the human body, and in particular, adhesion occurs at a frequency of about 70 to 95% after open surgery. In the case of adhesions that occur after surgery, it is known that foreign substances introduced, inflammatory reactions due to infection, bleeding at the surgical site, blood clotting, and rupture of the membrane. As you can see from the above causes of adhesion, bleeding has a large effect on the induction of adhesion, but there is no anti-adhesion agent that simultaneously exhibits the penetration and adhesion effect of active ingredients due to the increase in viscosity due to the temperature in the body. Currently used materials for hemostatic agents include bio-derived natural polymers, including polysaccharides, and non-bio-derived natural polymers. These materials are used alone or in a specific structure.
구체적으로 미국 특허 제7,262,181호에는 메틸 셀룰로오스, 에틸셀룰로오스, 하이드록시에틸 셀룰로오스와 같은 수용성 셀룰로오스 에테르 유도체로 구성된 지혈재료에 대하여 기재하고 있으며, 그 구조는 섬유, 직물, 부직포, 스폰지, 필름등의 형태이다. 상기와 같은 하이드로겔, 섬유, 폼, 부직포 등의 형태를 갖는 지혈제는 제품의 상처 부위에 빠르고 정확하게 도포되기 어려우며, 처치 시 의료진의 접촉에 의한 감염의 위험이 있어 효과가 제대로 발현되기 어렵다.Specifically, U.S. Patent No. 7,262,181 describes a hemostatic material composed of water-soluble cellulose ether derivatives such as methyl cellulose, ethyl cellulose, and hydroxyethyl cellulose, the structure of which is in the form of fibers, fabrics, non-woven fabrics, sponges, films, etc. . Hemostatic agents having the form of hydrogels, fibers, foams, and non-woven fabrics as described above are difficult to be applied quickly and accurately to the wound area of the product, and there is a risk of infection due to contact with medical personnel during treatment, so that the effect is difficult to be properly expressed.
필름이나 멤브레인 형태의 유착방지막을 이용할 경우 가장 큰 단점은 적용 부위에서 유착방지막의 이동을 막기위해 봉합사를 이용해 주변 조직과 봉합해야 하므로 봉합 부위에서 조직 유착이 빈번하게 일어난다는 점과 적용부위가 복잡하거나 미세한 부분, 도관 형태의 부분에는 도입이 어렵다는 점 등이 있다. 이를 극복하기 위하여 겔 형태의 카복시메틸셀룰로오스, 덱스트란70 (dextran 70), 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체 (polyethylene oxide-polypropylene oxide- polyethylene oxide)로 제조한 Flowgel, 폴리락틱산을 기본으로 한 Adcon-L (Gliatech), 히알루론산을 기본으로 한 Intercoat, 스프레이 형태의 폴리에틸렌옥사이드를 기본으로 한 Spraygel 등이 시판되고 있다.The biggest disadvantage of using a film or membrane type anti-adhesion film is that the adhesion of the tissue frequently occurs at the site of suture, because the sutures must be sutured with the surrounding tissue to prevent movement of the anti-adhesion film at the application site. It is difficult to introduce a fine part or a conduit type part. In order to overcome this, Flowgel, polylactic acid made of carboxymethyl cellulose, dextran 70, polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer (polyethylene oxide-polypropylene oxide- polyethylene oxide) Adcon-L (Gliatech) as a base, Intercoat based on hyaluronic acid, and Spraygel based on polyethylene oxide in the form of a spray are commercially available.
그러나, 겔 형태의 유착방지제의 경우에는 일반적으로 수술 부위의 상처 치유가 7일 정도 걸리는 것으로 알려져 있는데 상처가 치유되기 전에 체내(수용액상) 쉽게 분해/흡수되어 유착방지제로서의 효능이 낮은 문제점을 가지고 있다. (J. M. Becker, et al., presented at clinical congress of Am. College of surgeon, New of leans, October 22 (1995)).However, in the case of an anti-adhesion agent in the form of a gel, it is generally known that wound healing at the surgical site takes about 7 days, but it is easily decomposed / absorbed in the body (aqueous phase) before the wound is healed and has a problem of low efficacy as an anti-adhesion agent. . (J. M. Becker, et al., Presented at clinical congress of Am. College of surgeon, New of leans, October 22 (1995)).
이상과 같이, 수술 후 발생하는 조직 유착방지에 대하여 많은 연구가 진행되고 있지만 상기 문제점을 개선하지 못한 기존 형태의 유착방지제들을 사용할 경우 고가의 비용에도 불구하고 상응하는 효과를 나타내기 어려워 새로운 개념의 유착방지제에 대한 개발이 여전히 요구되는 실정이다.As described above, although many studies have been conducted on the prevention of tissue adhesion after surgery, it is difficult to exhibit a corresponding effect despite the high cost when using the existing types of adhesion prevention agents that have not improved the above problems, but a new concept of adhesion is achieved. The development of preventive agents is still required.
본 발명의 목적은 조직유착 억제성능을 갖는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 기본 구조체로 하고, 수불용성 히알루론산, 소듐알지네이트를 블랜딩하여 체내 상처 부위에 고르게 도포되는 조직유착 방지용 하이드로겔 조성물을 제공하는 조직유착 방지용 하이드로겔 조성물 및 그 제조방법을 제공하는 것이다.The object of the present invention is a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer having a tissue adhesion inhibiting function as a basic structure, and water-insoluble hyaluronic acid and sodium alginate are blended to prevent tissue adhesion that is evenly applied to the wounds in the body. It is to provide a hydrogel composition for preventing tissue adhesion and a method for preparing the gel composition.
또한, 본 발명의 다른 목적은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체의 녹는점 및 고분자상호간의 반발력을 이용하여 난용성 항암제를 안정적으로 방출하는 조직유착 방지용 하이드로겔 조성물 및 그 제조방법을 제공하는 것이다.In addition, another object of the present invention is a hydrogel composition for preventing tissue adhesion to stably release a poorly soluble anti-cancer agent using a melting point of a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer and a repulsive force between polymers, and a method for manufacturing the same Is to provide.
또한, 본 발명의 다른 목적은 생분해성 고분자가 함유되어 우수한 생분해성을 나타내는 조직유착 방지용 하이드로겔 조성물 및 그 제조방법을 제공하는 것이다.In addition, another object of the present invention is to provide a hydrogel composition for preventing tissue adhesion and a method of manufacturing the biodegradable polymer containing excellent biodegradability.
본 발명의 목적은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체, 수불용성 히알루론산, 소듐알지네이트 및 정제수로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물을 제공함에 의해 달성된다.The object of the present invention is achieved by providing a hydrogel composition for preventing tissue adhesion, characterized in that it consists of a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer, water-insoluble hyaluronic acid, sodium alginate and purified water.
본 발명의 바람직한 특징에 따르면, 상기 조직유착방지용 하이드로겔 조성물은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체 15 내지 30 중량%, 수불용성 히알루론산 2.5 내지 4.5 중량%, 소듐알지네이트 0.1 내지 1 중량% 및 정제수 잔량으로 이루어지는 것으로 한다.According to a preferred feature of the present invention, the hydrogel composition for preventing tissue adhesion is polyethylene oxide-polypropylene oxide-polyethylene oxide
본 발명의 더 바람직한 특징에 따르면, 상기 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체는 분자량이 1 내지 500kDa인 것으로 한다.According to a more preferred feature of the present invention, the polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer has a molecular weight of 1 to 500 kDa.
본 발명의 더욱 바람직한 특징에 따르면, 상기 수불용성 히알루론산은 에탄올 수용액 95 내지 99 중량%에 분자량이 500 내지 3000kDa인 히알루론산 1 내지 5 중량%를 혼합하여 혼합물을 제조하고, 상기 혼합물에 함유된 히알루론산 100 중량부 대비 및 가교제 0.02 내지 0.1 중량부를 더 혼합하여 이루어지는 것으로 한다.According to a more preferred feature of the present invention, the water-insoluble hyaluronic acid is prepared by mixing 1 to 5% by weight of hyaluronic acid having a molecular weight of 500 to 3000 kDa in 95 to 99% by weight of an ethanol aqueous solution, and the hyaluronic acid contained in the mixture. It is supposed to be made by further mixing 100 parts by weight of lactic acid and 0.02 to 0.1 parts by weight of a crosslinking agent.
본 발명의 더욱 더 바람직한 특징에 따르면, 상기 에탄올 수용액은 pH가 9.5 내지 13이고, 질량농도가 70 내지 80%인 것으로 한다.According to a still more preferred feature of the present invention, the aqueous ethanol solution has a pH of 9.5 to 13 and a mass concentration of 70 to 80%.
본 발명의 더욱 더 바람직한 특징에 따르면, 상기 가교제는 1,4-부탄디올디글리시딜에테르로 이루어지는 것으로 한다.According to a still more preferred feature of the present invention, the crosslinking agent is composed of 1,4-butanediol diglycidyl ether.
본 발명의 더욱 더 바람직한 특징에 따르면, 상기 조직유착 방지용 하이드로겔 조성물에는 상기 조직유착 방지용 하이드로겔 조성물 100 중량부 대비 난용성 항암제 0.1 내지 10 중량부가 더 함유되며, 상기 난용성 항암제는 도세탁셀, 도세탁셀 수화물, 파클리탁셀, 파클리탁셀 수화물, 카페시타빈 및 카페시타빈 수화물로 이루어진 그룹에서 선택된 하나로 이루어지는 것으로 한다.According to a still more preferred feature of the present invention, the hydrogel composition for preventing tissue adhesion further contains 0.1 to 10 parts by weight of a poorly soluble anticancer agent compared to 100 parts by weight of the hydrogel composition for preventing tissue adhesion, and the poorly soluble anticancer agent is docetaxel, docetaxel hydrate , Paclitaxel, paclitaxel hydrate, capecitabine and capecitabine hydrate.
본 발명의 더욱 더 바람직한 특징에 따르면, 상기 조직유착 방지용 하이드로겔 조성물에는 상기 조직유착 방지용 하이드로겔 조성물에 함유된 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체 100 중량부 대비 생분해성 고분자 10 내지 50 중량부가 더 함유되며, 상기 생분해성 고분자는 PLLA(Poly-L-lactic-Acid), PLGA(poly-lactic-co -glycolic acid), PDO(Polydioxanone) 및 PCL(polycaprolactone)으로 이루어진 그룹에서 선택된 하나로 이루어지는 것으로 한다.According to a still more preferred feature of the present invention, the hydrogel composition for preventing tissue adhesion has 10 to 50 biodegradable polymers compared to 100 parts by weight of polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer contained in the hydrogel composition for preventing tissue adhesion. Further parts by weight, the biodegradable polymer is made of one selected from the group consisting of poly-l-lactic-acid (PLLA), poly-lactic-co-glycolic acid (PLGA), polydioxanone (PDO) and polycaprolactone (PCL) It is assumed.
또한, 본 발명의 목적은 분자량이 1 내지 500kDa인 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 60 내지 100℃의 온도에서 1 내지 2시간 동안 가열하여 용해하는 공중합체용해단계, 상기 공중합체용해단계를 통해 제조된 용해물에 수불용성 히알루론산을 혼합하고, 10 내지 20℃의 온도로 교반하는 히알루론산혼합단계 및 상기 히알루론산혼합단계를 통해 제조된 혼합물에 소듐알지네이트를 혼합하고 5 내지 20℃의 온도로 교반하는 소듐알지네이트혼합단계로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물의 제조방법을 제공함에 의해서도 달성될 수 있다.In addition, the object of the present invention is a copolymer dissolving step in which the polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer having a molecular weight of 1 to 500 kDa is dissolved by heating at a temperature of 60 to 100 ° C. for 1 to 2 hours, the copolymer. Water-insoluble hyaluronic acid is mixed with the lysate prepared through the dissolving step, sodium alginate is mixed with the mixture prepared through the hyaluronic acid mixing step and the hyaluronic acid mixing step of stirring at a temperature of 10 to 20 ° C., and 5 to 20. It can also be achieved by providing a method of manufacturing a hydrogel composition for preventing tissue adhesion, characterized in that consisting of a sodium alginate mixing step of stirring at a temperature of ℃.
본 발명의 바람직한 특징에 따르면, 상기 공중합체용해단계와 상기 히알루론산혼합단계 사이에는 상기 공중합체용해단계를 통해 제조된 용해물에 난용성 항암제를 혼합하는 난용성항암제혼합단계가 더 진행되며, 상기 난용성 항암제는 도세탁셀, 도세탁셀 수화물, 파클리탁셀, 파클리탁셀 수화물, 카페시타빈 및 카페시타빈 수화물로 이루어진 그룹에서 선택된 하나로 이루어지는 것으로 한다.According to a preferred feature of the present invention, between the copolymer dissolving step and the hyaluronic acid mixing step, a poorly soluble anticancer agent mixing step of mixing a poorly soluble anticancer agent into the lysate prepared through the copolymer dissolving step further proceeds, the The poorly soluble anticancer agent is to be composed of one selected from the group consisting of docetaxel, docetaxel hydrate, paclitaxel, paclitaxel hydrate, capecitabine and capecitabine hydrate.
본 발명의 더 바람직한 특징에 따르면, 상기 공중합체용해단계와 상기 히알루론산혼합단계 사이에는 상기 공중합체용해단계를 통해 제조된 용해물에 생분해성 고분자를 혼합하는 생분해성고분자혼합단계가 더 진행되며, 상기 생분해성 고분자는 PLLA(Poly-L-lactic-Acid), PLGA(poly-lactic-co -glycolic acid), PDO(Polydioxanone) 및 PCL(polycaprolactone)으로 이루어진 그룹에서 선택된 하나로 이루어지는 것으로 한다.According to a more preferred feature of the present invention, between the copolymer dissolving step and the hyaluronic acid mixing step, a biodegradable polymer mixing step in which a biodegradable polymer is mixed with a lysate produced through the copolymer dissolving step further proceeds, The biodegradable polymer is to be made of one selected from the group consisting of poly-L-lactic-Acid (PLLA), poly-lactic-co-glycolic acid (PLGA), polydioxanone (PDO) and polycaprolactone (PCL).
본 발명에 따른 조직유착 방지용 하이드로겔 조성물 및 그 제조방법은 조직유착 억제성능을 갖는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 기본 구조체로 하고, 수불용성 히알루론산, 소듐알지네이트를 블랜딩하여 체내 상처 부위에 고르게 도포되는 조직유착 방지용 하이드로겔 조성물을 제공하는 탁월한 효과를 나타낸다.The hydrogel composition for preventing tissue adhesion according to the present invention and a method for manufacturing the same are based on a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer having tissue adhesion inhibiting performance, and blended water-insoluble hyaluronic acid and sodium alginate in the body It shows an excellent effect of providing a hydrogel composition for preventing tissue adhesion evenly applied to the wound.
또한, 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체의 녹는점 및 고분자상호간의 반발력을 이용하여 난용성 항암제를 안정적으로 방출하는 조직유착 방지용 하이드로겔 조성물을 제공하는 탁월한 효과를 나타낸다.In addition, it exhibits an excellent effect of providing a hydrogel composition for preventing tissue adhesion that stably releases a poorly soluble anticancer agent by using the melting point of the polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer and the repulsive force between polymers.
또한, 생분해성 고분자가 함유되어 우수한 생분해성을 나타내는 조직유착 방지용 하이드로겔 조성물을 제공하는 탁월한 효과를 나타낸다.In addition, it exhibits an excellent effect of providing a biodegradable polymer-containing hydrogel composition for preventing tissue adhesion, which shows excellent biodegradability.
도 1은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체의 농도 함량에 따른 조직유착 방지용 하이드로겔 조성물 점도 변화를 나타낸 그래프이다.
도 2는 약물 투여에 따른 종양 역제 효능을 비교 분석한 그래프인데, Vehicle는 PBS 단독이며, DTX 10mpk는 도세탁셀 10mg, DTX-88 10mpk는 조직유착 방지용 하이드로겔 조성물에 함유된 도세탁셀 10mg, DTX-88 20mpk는 조직유착 방지용 하이드로겔 조성물에 함유된 도세탁셀 20mg을 나타내며, 직접 환부에 투입하고 30일간의 종양크기 변화를 관찰한 결과이다.
도 3은 환부를 절개하여 직접 약물 및 조직유착 방지용 하이드로겔 조성물을 투입한 후 종양의 크기를 관찰한 자료인데, Vehicle는 PBS 단독이며, DTX 10mpk는 도세탁셀 10mg, DTX-88 10mpk는 조직유착 방지용 하이드로겔 조성물에 함유된 도세탁셀 10mg, DTX-88 20mpk는 조직유착 방지용 하이드로겔 조성물에 함유된 도세탁셀 20mg을 나타낸 것이다.
도 4는 환부를 절개하여 직접 약물 및 조직유착 방지용 하이드로겔 조성물을 투입한 후 30일 이후에 종양의 크기를 관찰한 자료로, Vehicle는 PBS 단독이며, DTX 10mpk는 도세탁셀 10mg, DTX-88 10mpk는 조직유착 방지용 하이드로겔 조성물에 함유된 도세탁셀 10mg, DTX-88 20mpk는 조직유착 방지용 하이드로겔 조성물에 함유된 도세탁셀 20mg을 나타낸 것이다.
도 5는 도 4의 Vehicle(PBS)만 환부에 주입하였을 때 개체의 사진이다.
도 6은 도 4의 DTX-88 10mpk를 환부에 주입하였을 때 개체의 사진이다.
도 7은 도 4에서 환부를 절개한 후 주위 장기의 유착 유무를 확인한 자료이다.
도 8은 도 4의 DTX-88 20mpk를 환부에 주입하였을 때 개체의 사진이다.
도 9의 (a)는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 공중합체가 15중량%일 때 생분해성 고분자(PLLA)의 평균입자 사이즈를 입경분석기로 측정한 자료이다. (b)는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드가 20 중량%일 때 생분해성 고분자(PLLA)의 평균입자 사이즈를 입경분석기로 측정한 자료이다. (c)는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드가 25 중량%일 때 생분해성 고분자(PLLA)의 평균입자 사이즈를 입경분석기로 측정한 자료이다.
도 10의 (a)는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드가 20 중량%이며, 생분해성 고분자인 PLLA가 함유된 조직유착 방지용 하이드로겔 조성물을 광학현미경으로 측정한 사진이다. (b)는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드가가 20 중량%이며 생분해성 고분자인 PLGA가 함유된 조직유착 방지용 하이드로겔 조성물을 광학현미경으로 측정한 사진이다. (c)는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드가 20 중량%이며 생분해성 고분자인 PDO가 함유된 조직유착 방지용 하이드로겔 조성물을 광학현미경으로 측정한 사진이다. (d)는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드가 20 중량%이며 생분해성 고분자인 PCL가 함유된 조직유착 방지용 하이드로겔 조성물을 광학현미경으로 측정한 사진이다.1 is a graph showing the viscosity change of the hydrogel composition for preventing tissue adhesion according to the concentration content of the polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer.
Figure 2 is a graph comparing the efficacy of tumor reversal according to drug administration, Vehicle is PBS alone, DTX 10mpk is docetaxel 10mg, DTX-88 10mpk is docetaxel 10mg, DTX-88 20mpk contained in the hydrogel composition for preventing tissue adhesion Indicates 20 mg of docetaxel contained in the hydrogel composition for preventing tissue adhesion, and is a result of observing changes in tumor size over 30 days after being directly injected into the affected area.
Figure 3 is the data to observe the size of the tumor after injecting the hydrogel composition for direct drug and tissue adhesion prevention by incision in the affected area, Vehicle is PBS alone, DTX 10mpk is docetaxel 10mg, DTX-88 10mpk is tissue adhesion prevention hydro Docetaxel 10mg, DTX-88 20mpk contained in the gel composition shows 20mg docetaxel contained in the hydrogel composition for preventing tissue adhesion.
4 is a data obtained by observing the size of the tumor 30 days after the injection of the hydrogel composition for preventing drug and tissue adhesion directly by cutting the affected area, Vehicle is PBS alone, DTX 10mpk is docetaxel 10mg, DTX-88
5 is a photograph of an object when only the vehicle (PBS) of FIG. 4 is injected into the affected area.
6 is a photograph of an object when the DTX-88 10mpk of FIG. 4 is injected into the affected area.
7 is data confirming the presence or absence of adhesions of surrounding organs after incision in the affected area in FIG. 4.
FIG. 8 is a photograph of an object when the DTX-88 20mpk of FIG. 4 is injected into the affected area.
9 (a) is data obtained by measuring the average particle size of the biodegradable polymer (PLLA) when the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer is 15% by weight with a particle size analyzer. (b) is a data obtained by measuring the average particle size of the biodegradable polymer (PLLA) when the polyethylene oxide-polypropylene oxide-polyethylene oxide is 20% by weight with a particle size analyzer. (c) is a data obtained by measuring the average particle size of the biodegradable polymer (PLLA) when the polyethylene oxide-polypropylene oxide-polyethylene oxide is 25 wt%.
FIG. 10 (a) is a photograph of polyethylene oxide-polypropylene oxide-polyethylene oxide having a weight of 20% by weight, and measuring the hydrogel composition for preventing tissue adhesion with PLLA, a biodegradable polymer, with an optical microscope. (b) is a photograph of a polyethylene oxide-polypropylene oxide-polyethylene oxide value of 20 wt% and a biodegradable polymer-containing PLGA-containing hydrogel composition for preventing tissue adhesion with an optical microscope. (c) is a photograph of polyethylene oxide-polypropylene oxide-polyethylene oxide having a weight of 20% by weight and a biodegradable polymer PDO-containing hydrogel composition for preventing tissue adhesion with an optical microscope. (d) is a photograph of polyethylene oxide-polypropylene oxide-polyethylene oxide having a weight of 20% by weight and a biodegradable polymer PCL-containing hydrogel composition for preventing tissue adhesion with an optical microscope.
이하에는, 본 발명의 바람직한 실시예와 각 성분의 물성을 상세하게 설명하되, 이는 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 발명을 용이하게 실시할 수 있을 정도로 상세하게 설명하기 위한 것이지, 이로 인해 본 발명의 기술적인 사상 및 범주가 한정되는 것을 의미하지는 않는다.Hereinafter, the preferred embodiment of the present invention and the physical properties of each component will be described in detail, but it is intended to be described in detail so that a person skilled in the art to which the present invention pertains can easily implement the invention. This does not mean that the technical spirit and scope of the present invention is limited.
본 발명에 따른 조직유착 방지용 하이드로겔 조성물은 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체, 수불용성 히알루론산, 소듐알지네이트 및 정제수로 이루어지며, 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체 15 내지 30 중량%, 수불용성 히알루론산 2.5 내지 4.5 중량%, 소듐알지네이트 0.1 내지 1 중량% 및 정제수 잔량으로 이루어지는 것이 바람직하다.The hydrogel composition for preventing tissue adhesion according to the present invention consists of a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer, water-insoluble hyaluronic acid, sodium alginate and purified water, and a polyethylene oxide-polypropylene oxide-polyethylene
상기 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체는 15 내지 30 중량%가 함유되며, 분자량이 1 내지 500kDa인 것을 사용하는 것이 바람직한데, 본 발명에 따른 조직유착 방지용 하이드로겔 조성물의 주재료가 되는 성분으로, 생체적합성을 가지며 우수한 조직유착 방지 효과를 나타내는 하이드로겔 조성물을 제공하는 역할을 한다.The polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer contains 15 to 30% by weight, it is preferable to use a molecular weight of 1 to 500kDa, which is the main material of the hydrogel composition for preventing tissue adhesion according to the present invention As a component, it has a biocompatibility and serves to provide a hydrogel composition that exhibits an excellent anti-tissue adhesion effect.
또한, 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체의 녹는점 및 삼원 공중합체를 구성하는 고분자 물질 간의 반발력을 이용하여 난용성 항암제의 나노화를 통해 난용성 항암제가 안정적으로 방출되는 조직유착 방지용 하이드로겔 조성물을 제공하는 역할을 한다.In addition, by using the melting point of the polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer and the repulsive force between the polymer materials constituting the ternary copolymer, hydrolysis for preventing tissue adhesion through which the poorly soluble anticancer agent is stably released by nano-forming the poorly soluble anticancer agent It serves to provide a gel composition.
또한, 상기의 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체는 녹는점 및 고분자상호간의 반발력을 이용하여 생분해성고분자를 무용매 상태에서 입자화할 수 있어, 생분해성이 우수한 조직유착 방지용 하이드로겔 조성물이 제조될 수 있도록 하는 역할을 한다.In addition, the above-mentioned polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer is capable of granulating biodegradable polymers in a solvent-free state by using a melting point and a repulsive force between polymers, thereby preventing biodegradability of tissue adhesion. It serves to help make it.
이때, 상기 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체의 함량이 15 중량% 미만이거나 30 중량%를 초과하게 되면 아래 도 1에 나타낸 것처럼, 가열된 상태에서 졸-겔 작용이 유발되지 않게 된다.At this time, when the content of the polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer is less than 15% by weight or exceeds 30% by weight, as shown in FIG. 1 below, the sol-gel action is not induced in the heated state. .
상기 수불용성 히알루론산은 2.5 내지 4.5 중량%가 함유되며, 피부보습효과, 피부재생, 향균효과를 나타낼 뿐만 아니라, 수불용성이기 때문에 본 발명에 따른 조직유착 방지용 하이드로겔 조성물의 형태안정성을 향상시키고 지혈작용의 역할을 한다.The water-insoluble hyaluronic acid contains 2.5 to 4.5% by weight, as well as exhibits a skin moisturizing effect, skin regeneration, and antibacterial effect, and because it is water-insoluble, improves the shape stability of the hydrogel composition for preventing tissue adhesion according to the present invention and prevents hemostasis It acts.
상기 수불용성 히알루론산은 에탄올 수용액 95 내지 99 중량%에 분자량이 500 내지 3000kDa인 히알루론산 1 내지 5 중량%를 혼합하여 혼합물을 제조하고, 상기 혼합물에 함유된 히알루론산 100 중량부 대비 및 가교제 0.02 내지 0.1 중량부를 더 혼합하여 제조된다.The water-insoluble hyaluronic acid is prepared by mixing 1 to 5% by weight of hyaluronic acid having a molecular weight of 500 to 3000kDa in 95 to 99% by weight of an ethanol aqueous solution, compared to 100 parts by weight of hyaluronic acid contained in the mixture and 0.02 to crosslinking agent It is prepared by further mixing 0.1 parts by weight.
이때, 상기 히알루론산으로는 소듐하이알루로네이트 (Sodium Hyaluronate)를 사용하는 것이 바람직하며, 상기 에탄올 수용액은 pH가 9.5 내지 13이고, 질량농도가 70 내지 80%인 것을 사용하는 것이 바람직하다.At this time, it is preferable to use sodium hyaluronate (Sodium Hyaluronate) as the hyaluronic acid, the ethanol aqueous solution is preferably a pH of 9.5 to 13, a mass concentration of 70 to 80%.
상기 에탄올 수용액의 질량농도가 70% 미만이면 히알루론산의 응집현상이 일어나며, 에탄올 수용액의 질량농도가 80%를 초과하게 되면 에탄올 성분을 제거하는 과정에서 히알루론산의 점도가 지나치게 증가하여 가교제가 부분적으로 급격히 반응하기 때문에 균일한 점도를 얻을 수 없게 된다.When the mass concentration of the ethanol aqueous solution is less than 70%, aggregation of hyaluronic acid occurs, and when the mass concentration of the ethanol aqueous solution exceeds 80%, the viscosity of the hyaluronic acid increases excessively in the process of removing the ethanol component, and the crosslinking agent partially Since it reacts rapidly, a uniform viscosity cannot be obtained.
이때, 상기 수불용성 히알루론산을 제조하는 과정에서는 음압을 0.1 내지 1atm으로 가하고, 교반속도는 50 내지 100rpm을 유지함과 동시에 가교제로는 1,4-부탄디올디글리시딜에테르를 사용하는 것이 바람직하다.At this time, in the process of preparing the water-insoluble hyaluronic acid, it is preferable to use a 1,4-butanediol diglycidyl ether as a crosslinking agent while adding a negative pressure of 0.1 to 1 atm and maintaining a stirring speed of 50 to 100 rpm.
상기 가교제의 함량이 0.02 중량부 미만이면 가교도가 낮아지며, 가교제의 함량이 0.1 중량부를 초과하게 되면 부분적으로 용액내에서 겔 현상이 유발되어 고른 혼합이 이루어지지 않는다.When the content of the crosslinking agent is less than 0.02 parts by weight, the degree of crosslinking is lowered, and when the content of the crosslinking agent exceeds 0.1 parts by weight, a gel phenomenon is partially induced in the solution, and even mixing is not achieved.
상기의 조건에서 교반을 진행하다가, 용액이 투명한 상태로 변하면 교반 및 음압을 제거한 상태에서 반응기 외부 온도를 40 내지 60℃로 유지한 상태에서 24시간 정체시킨 후에, 전체가 완료된 용액을 7±2kDa의 투석막을 사용하여 2일 내지 3일간 투석하는 과정을 통해 제조를 완료한다.After stirring under the above conditions, when the solution is changed to a transparent state, after standing for 24 hours in a state where the external temperature of the reactor is maintained at 40 to 60 ° C. while stirring and negative pressure are removed, the entire solution is 7 ± 2 kDa. The dialysis membrane is used to complete the preparation through dialysis for 2 to 3 days.
상기 소듐알지네이트는 0.1 내지 1 중량%가 함유되며, 본 발명에 따른 조직유착 방지용 하이드로겔 조성물에 유착방지 효과를 부여할 뿐만 아니라, 점도와 접착성을 향상시켜 체내 상처 부위에 고르게 도포되도록 하는 역할을 한다.The sodium alginate contains 0.1 to 1% by weight, as well as imparting an anti-adhesion effect to the hydrogel composition for preventing tissue adhesion according to the present invention, improves viscosity and adhesion, and serves to evenly apply to the wound area in the body. do.
이때, 상기 소듐알지네이트는 분자량이 300 내지 1000kDa인 것을 사용하는 것이 바람직하다.At this time, the sodium alginate is preferably used having a molecular weight of 300 to 1000kDa.
또한, 상기 소듐알지네이트의 함량이 0.1 중량% 미만이면 유착방지 효과를 구현할 수 없으며, 소듐알지네이트의 함량이 1 중량%를 초과하게 되면 본 발명에 따른 조직유착 방지용 하이드로겔 조성물의 점도가 지나치게 상승함과 동시에 하한 임계 용액 온도(LCST: Lower Critical Solution Temperature)를 증가시키게 된다.In addition, if the content of sodium alginate is less than 0.1% by weight, an anti-adhesion effect cannot be achieved, and when the content of sodium alginate exceeds 1% by weight, the viscosity of the hydrogel composition for preventing tissue adhesion according to the present invention is excessively increased. At the same time, the lower critical solution temperature (LCST) is increased.
상기의 소듐알지네이트를 혼합할 때는 교반기의 온도를 5 내지 20℃로 유지하는 것이 바람직하며 10 내지 15℃로 유지하는 것이 더욱 바람직한데, 교반기의 온도가 5℃ 미만이면 혼합물에 포함된 물이 부분적으로 빙결될 수 있으며, 교반기의 온도가 20℃를 초과하게 되면 혼합물의 점도가 급격하게 상승하여 버블현상으로 인해 혼합이 균일하게 이루어지지 않는다.When mixing the sodium alginate, the temperature of the stirrer is preferably maintained at 5 to 20 ° C, and more preferably 10 to 15 ° C. If the temperature of the stirrer is less than 5 ° C, the water contained in the mixture is partially It can be frozen, and when the temperature of the stirrer exceeds 20 ° C, the viscosity of the mixture rises rapidly and mixing is not uniform due to the bubble phenomenon.
또한, 상기 조직유착 방지용 하이드로겔 조성물에는 상기 조직유착 방지용 하이드로겔 조성물 100 중량부 대비 난용성 항암제 0.1 내지 10 중량부가 더 함유될 수도 있는데, 상기 난용성 항암제는 도세탁셀, 도세탁셀 수화물, 파클리탁셀, 파클리탁셀 수화물, 카페시타빈 및 카페시타빈 수화물로 이루어진 그룹에서 선택된 하나로 이루어지며, 조직유착 방지 효과 뿐만 아니라, 각종 암 수술 이후에 수술부위에 항암제가 지속적으로 용출되어 우수한 항암 효과를 나타내는 하이드로겔 조성물을 제공하는 역할을 한다.In addition, the hydrogel composition for preventing tissue adhesion may further contain 0.1 to 10 parts by weight of a poorly soluble anticancer agent compared to 100 parts by weight of the hydrogel composition for preventing tissue adhesion, wherein the poorly soluble anticancer agent is docetaxel, docetaxel hydrate, paclitaxel, paclitaxel hydrate, It is made of one selected from the group consisting of capecitabine and capecitabine hydrate, and serves to provide a hydrogel composition that exhibits excellent anticancer effects by continuously dissolving anti-cancer agents on the surgical site after various cancer operations, as well as preventing tissue adhesion. Do it.
또한, 상기 조직유착 방지용 하이드로겔 조성물에는 상기 조직유착 방지용 하이드로겔 조성물에 함유된 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체 100 중량부 대비 생분해성 고분자 10 내지 50 중량부가 더 함유되며, 상기 생분해성 고분자는 PLLA(Poly-L-lactic-Acid), PLGA(poly-lactic-co -glycolic acid), PDO(Polydioxanone) 및 PCL(polycaprolactone)으로 이루어진 그룹에서 선택된 하나로 이루어지는데, 상기의 성분으로 이루어지는 생분해성 고분자가 함유되면 생분해성이 우수한 조직유착 방지용 하이드로겔 조성물이 제공된다.In addition, the hydrogel composition for preventing tissue adhesion further contains 10 to 50 parts by weight of a biodegradable polymer compared to 100 parts by weight of a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer contained in the hydrogel composition for preventing tissue adhesion, and the biodegradation The sex polymer consists of one selected from the group consisting of poly-l-lactic-acid (PLLA), poly-lactic-co-glycolic acid (PLGA), polydioxanone (PDO) and polycaprolactone (PCL), which is biodegradable consisting of the above components. When the sex polymer is contained, a hydrogel composition for preventing bioadhesion is provided.
이때, 상기 생분해성 고분자의 함량이 10 중량부 미만이면 상기의 효과가 미미하며, 상기 생분해성 고분자의 함량이 50 중량부를 초과하게 되면 본 발명에 따른 조직유착 방지용 하이드로겔 조성물의 형태안정성이 저하될 수 있다.At this time, if the content of the biodegradable polymer is less than 10 parts by weight, the above effect is negligible, and when the content of the biodegradable polymer exceeds 50 parts by weight, the morphological stability of the hydrogel composition for preventing tissue adhesion according to the present invention is deteriorated. You can.
또한, 본 발명에 따른 조직유착 방지용 하이드로겔 조성물의 제조방법은 분자량이 1 내지 500kDa인 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 60 내지 100℃의 온도에서 1 내지 2시간 동안 가열하여 용해하는 공중합체용해단계, 상기 공중합체용해단계를 통해 제조된 용해물에 수불용성 히알루론산을 혼합하고, 10 내지 20℃의 온도로 교반하는 히알루론산혼합단계 및 상기 히알루론산혼합단계를 통해 제조된 혼합물에 소듐알지네이트를 혼합하고 5 내지 20℃의 온도로 교반하는 소듐알지네이트혼합단계로 이루어진다.In addition, the method for preparing a hydrogel composition for preventing tissue adhesion according to the present invention is dissolved by heating a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer having a molecular weight of 1 to 500 kDa at a temperature of 60 to 100 ° C. for 1 to 2 hours. The copolymer dissolving step, a mixture prepared through the hyaluronic acid mixing step and the hyaluronic acid mixing step of mixing the water-insoluble hyaluronic acid in the lysate prepared through the copolymer dissolving step, and stirring at a temperature of 10 to 20 ℃ It is made of a sodium alginate mixing step of mixing with sodium alginate and stirring to a temperature of 5 to 20 ℃.
상기 공중합체용해단계는 분자량이 1 내지 500kDa인 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 60 내지 100℃의 온도에서 1 내지 2시간 동안 가열하여 이루어지는데, 이때, 상기 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체의 본 발명에 따른 조직유착 방지용 하이드로겔 조성물 전체 중 15 내지 30 중량%를 나타내도록 사용되는 것이 바람직한데, 삼원 공중합체의 함량이 15 중량% 미만이거나 30 중량%를 초과하게 되면 아래 도 1에 나타낸 것처럼, 가열된 상태에서 졸-겔 작용이 유발되지 않게 된다.The copolymer dissolving step consists of heating a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer having a molecular weight of 1 to 500 kDa at a temperature of 60 to 100 ° C for 1 to 2 hours, wherein the polyethylene oxide-polypropylene The oxide-polyethylene oxide ternary copolymer is preferably used to represent 15 to 30% by weight of the total hydrogel composition for preventing tissue adhesion according to the present invention, the content of the ternary copolymer being less than 15% by weight or more than 30% by weight If so, as shown in Figure 1 below, the sol-gel action is not induced in the heated state.
상기 히알루론산혼합단계는 상기 공중합체용해단계를 통해 제조된 용해물에 수불용성 히알루론산을 혼합하고, 10 내지 20℃의 온도로 교반하는 단계로, 상기 수불용성 히알루론산의 함량은 본 발명에 따른 조직유착 방지용 하이드로겔 조성물 전체 중 수불용성 히알루론산의 함량이 2.5 내지 4.5 중량%를 나타내도록 혼합되는 것이 바람직하다.The hyaluronic acid mixing step is a step of mixing water-insoluble hyaluronic acid in the lysate prepared through the copolymer dissolving step, and stirring at a temperature of 10 to 20 ° C. The content of the water-insoluble hyaluronic acid is according to the present invention. It is preferable that the content of the water-insoluble hyaluronic acid in the whole hydrogel composition for preventing tissue adhesion is 2.5 to 4.5% by weight.
이때, 상기 수불용성 히알루론산의 제조과정은 상기 조직유착 방지용 하이드로겔 조성물의 설명 부분에 기재된 내용과 동일하므로, 이에 대한 설명은 생략하기로 한다.At this time, since the manufacturing process of the water-insoluble hyaluronic acid is the same as described in the description of the hydrogel composition for preventing tissue adhesion, a description thereof will be omitted.
상기 소듐알지네이트혼합단계는 상기 히알루론산혼합단계를 통해 제조된 혼합물에 소듐알지네이트를 혼합하고 5 내지 20℃의 온도로 교반하는 단계로, 이때, 상기 소듐알지네이트는 분자량이 300 내지 1000kDa인 것을 사용하는 것이 바람직하다.The sodium alginate mixing step is a step of mixing sodium alginate with a mixture prepared through the hyaluronic acid mixing step and stirring at a temperature of 5 to 20 ° C, wherein the sodium alginate has a molecular weight of 300 to 1000 kDa. desirable.
또한, 상기 소듐알지네이트혼합단계에서 소듐알지네이트의 혼합량은 본 발명에 따른 조직유착 방지용 하이드로겔 조성물 전체 중 소듐알지네이트의 함량이 0.1 내지 1 중량%를 나타내도록 혼합되는 것이 바람직한데, 상기 소듐알지네이트의 함량이 0.1 중량% 미만이면 유착방지 효과를 구현할 수 없으며, 소듐알지네이트의 함량이 1 중량%를 초과하게 되면 본 발명에 따른 조직유착 방지용 하이드로겔 조성물의 점도가 지나치게 상승함과 동시에 하한 임계 용액 온도(LCST: Lower Critical Solution Temperature)를 증가시키게 된다.In addition, in the mixing step of sodium alginate, the mixing amount of sodium alginate is preferably mixed so that the content of sodium alginate in the whole hydrogel composition for preventing tissue adhesion according to the present invention is 0.1 to 1% by weight, the content of sodium alginate is If it is less than 0.1% by weight, the anti-adhesion effect cannot be realized, and when the content of sodium alginate exceeds 1% by weight, the viscosity of the hydrogel composition for preventing tissue adhesion according to the present invention is too high and at the same time the lower limit solution temperature (LCST: Lower Critical Solution Temperature).
또한, 상기 소듐알지네이트혼합단예게서 상기 교반 온도가 5℃ 미만이면 혼합물에 포함된 물이 부분적으로 빙결될 수 있으며, 교반 온도가 20℃를 초과하게 되면 혼합물의 점도가 급격하게 상승하여 버블현상으로 인해 혼합이 균일하게 이루어지지 않는다.In addition, in the sodium alginate mixture stage, when the stirring temperature is less than 5 ° C, water contained in the mixture may be partially frozen, and when the stirring temperature exceeds 20 ° C, the viscosity of the mixture rapidly rises due to bubble phenomenon. Mixing is not uniform.
또한, 상기 공중합체용해단계와 상기 히알루론산혼합단계 사이에는 상기 공중합체용해단계를 통해 제조된 용해물에 난용성 항암제를 혼합하는 난용성항암제혼합단계가 더 진행될 수도 있는데, 상기 난용성 항암제는 도세탁셀, 도세탁셀 수화물, 파클리탁셀, 파클리탁셀 수화물, 카페시타빈 및 카페시타빈 수화물로 이루어진 그룹에서 선택된 하나로 이루어지는 것이 바람직하다.In addition, between the copolymer dissolving step and the hyaluronic acid mixing step, a poorly soluble anticancer agent mixing step of mixing a poorly soluble anticancer agent into the lysate prepared through the copolymer dissolving step may be further performed, wherein the poorly soluble anticancer agent is docetaxel , Docetaxel hydrate, paclitaxel, paclitaxel hydrate, capecitabine and capecitabine hydrate are preferably one selected from the group consisting of.
이때, 상기 난용성항암제혼합단계에서 사용되는 난용성 항암제의 함량 및 역할은 상기 조직유착 방지용 하이드로겔 조성물의 설명 부분에 기재된 내용과 동일하므로, 이에 대한 설명은 생략하기로 한다.At this time, since the content and role of the poorly soluble anticancer agent used in the mixing step of the poorly soluble anticancer agent is the same as described in the description of the hydrogel composition for preventing tissue adhesion, a description thereof will be omitted.
또한, 상기 공중합체용해단계와 상기 히알루론산혼합단계 사이에는 상기 공중합체용해단계를 통해 제조된 용해물에 생분해성 고분자를 혼합하는 생분해성고분자혼합단계가 더 진행될 수도 있는데, 상기 생분해성 고분자는 PLLA(Poly-L-lactic-Acid), PLGA(poly-lactic-co -glycolic acid), PDO(Polydioxanone) 및 PCL(polycaprolactone)으로 이루어진 그룹에서 선택된 하나로 이루어지는 것이 바람지하다.In addition, between the copolymer dissolving step and the hyaluronic acid mixing step, a biodegradable polymer mixing step in which a biodegradable polymer is mixed with a lysate prepared through the copolymer dissolving step may be further performed. (Poly-L-lactic-Acid), PLGA (poly-lactic-co-glycolic acid), PDO (Polydioxanone) and PCL (polycaprolactone) is selected from the group consisting of one.
이때, 상기 생분해성고분자혼합단계에서 사용되는 생분해성 고분자의 함량 및 역할은 상기 조직유착 방지용 하이드로겔 조성물의 설명 부분에 기재된 내용과 동일하므로, 이에 대한 설명은 생략하기로 한다.At this time, since the content and role of the biodegradable polymer used in the biodegradable polymer mixing step are the same as those described in the description of the hydrogel composition for preventing tissue adhesion, a description thereof will be omitted.
이하에서는, 본 발명에 따른 조직유착 방지용 하이드로겔 조성물의 제조방법 및 그 제조방법을 통해 제조된 조직유착 방지용 하이드로겔 조성물의 물성을 실시예를 들어 설명하기로 한다.Hereinafter, a method for preparing a hydrogel composition for preventing tissue adhesion according to the present invention and properties of a hydrogel composition for preventing tissue adhesion prepared through the manufacturing method will be described with reference to examples.
<표 1> 조직유착 방지용 하이드로겔 조성물의 제조<Table 1> Preparation of hydrogel composition for preventing tissue adhesion
<표 2> 도세탁셀이 함유된 조직유착 방지용 하이드로겔 조성물의 제조<Table 2> Preparation of hydrogel composition for preventing tissue adhesion containing docetaxel
<표 3> 파클리탁셀이 함유된 조직유착 방지용 하이드로겔 조성물의 제조<Table 3> Preparation of hydrogel composition for preventing tissue adhesion containing paclitaxel
<표 4> 카페시타빈이 함유된 조직유착 방지용 하이드로겔 조성물의 제조<Table 4> Preparation of hydrogel composition for preventing tissue adhesion containing capecitabine
<표 5> PLLA가 함유된 조직유착 방지용 하이드로겔 조성물의 제조<Table 5> Preparation of hydrogel composition for preventing tissue adhesion containing PLLA
삼원공중합체를 먼저 용해시킨 후 PLLA의 유리전이온도 부근에서 생분해성 고분자인 PLLA를 첨가하여 30분간 교반 후 제조하였다.After dissolving the terpolymer, the PLLA, a biodegradable polymer, was added near the glass transition temperature of PLLA and stirred for 30 minutes to prepare.
<표 6> PLGA가 함유된 조직유착 방지용 하이드로겔 조성물의 제조<Table 6> Preparation of hydrogel composition for preventing tissue adhesion containing PLGA
삼원공중합체를 먼저 용해시킨 후 PLGA의 유리전이온도 부근에서 생분해성 고분자를 첨가하여 30분간 교반 후 제조하였다.After dissolving the terpolymer, the biodegradable polymer was added near the glass transition temperature of PLGA and stirred for 30 minutes to prepare.
<표 7> PDO가 함유된 조직유착 방지용 하이드로겔 조성물의 제조<Table 7> Preparation of hydrogel composition for preventing tissue adhesion containing PDO
삼원공중합체를 먼저 용해시킨 후 PDO의 유리전이온도 부근에서 생분해성 고분자를 첨가하여 30분간 교반 후 제조하였다.After dissolving the terpolymer, the biodegradable polymer was added near the glass transition temperature of PDO and stirred for 30 minutes to prepare.
<표 8> PCL이 함유된 조직유착 방지용 하이드로겔 조성물의 제조<Table 8> Preparation of a hydrogel composition for preventing tissue adhesion containing PCL
삼원공중합체를 먼저 용해시킨 후 PCL의 유리전이온도 부근에서 생분해성 고분자를 첨가하여 30분간 교반 후 제조하였다.After dissolving the terpolymer, a biodegradable polymer was added near the glass transition temperature of PCL and stirred for 30 minutes to prepare.
<실시예 113> PLLA, PLGA, PDO, PCL입자의 제조<Example 113> Preparation of PLLA, PLGA, PDO, PCL particles
상기 실시예 65 내지 112에서 삼원 공중합체 대비 생분해성 고분자를 투입하여 입자화시킨 후 수불용성하이드로겔을 첨가하지않고 증류수로 3회이상 세척한 후에, -70℃ 이하에서 동결하고, -45℃와 1m bar에서 동결건조하여 입자를 제조하였다.In Examples 65 to 112, the biodegradable polymer was added to the ternary copolymer, followed by granulation, followed by washing with distilled water three or more times without adding a water-insoluble hydrogel, freezing at -70 ° C or lower, and freezing at -45 ° C and 1m. Freeze-dried at the bar to prepare particles.
<실험예 1><Experimental Example 1>
상기 실시예 1 내지 16에서 제조된 조직유착 방지용 하이드로겔 조성물의 균일성을 육안으로 확인하여 아래 표 9에 나타내었다.The uniformity of the hydrogel composition for preventing tissue adhesion prepared in Examples 1 to 16 was visually shown in Table 9 below.
<표 9>Table 9
상기 표 9에 나타낸 것처럼, 삼원 공중합체의 함량이 15 중량% 미만이거나 30 중량%를 초과하게 되면 하이드로겔 조성물의 상태는 균일하지 못하며, 수불용성 히알루론산의 농도가 2.5 중량% 미만이거나 4.5 중량%를 초과할때도 하이드로겔 조성물의 균일성이 확보되지 않는 것을 알 수 있다.As shown in Table 9, when the content of the ternary copolymer is less than 15% by weight or more than 30% by weight, the state of the hydrogel composition is not uniform, and the concentration of the water-insoluble hyaluronic acid is less than 2.5% by weight or 4.5% by weight. It can be seen that even when it exceeds, the uniformity of the hydrogel composition is not secured.
<실험예 2> 복합하이드로겔의 유착방지 효능 동물 실험 - 부검 시 육안소견<Experimental Example 2> Effect of anti-adhesion effect of complex hydrogels Animal experiment-Visual observation at autopsy
실험예 2는 상기 실시예 6, 7, 10, 11을 사용하여 조직 유착 방지, 국소 출혈에 대한 지혈 효과에 미치는 영향을 살펴본 것으로, 부검 시 육안소견의 관찰을 통하여 유착방지 효능을 알아보기 위한 실험을 실시하여 아래 표 12에 나타내었다.Experimental Example 2 was to examine the effect on the hemostatic effect on tissue bleeding prevention and local bleeding by using Examples 6, 7, 10, and 11 above, an experiment to determine the effect of preventing adhesion through observation of visual findings at autopsy It was carried out as shown in Table 12 below.
마취 후 수술 부위에 제모를 실시하고, 포비돈으로 소독 한 다음 복강의 정중선을 따라 4 내지 5 cm 절개하였다. 맹장을 꺼내어 가로 1cm×세로 2cm 크기로 bone burr를 이용하여 찰과상을 내고 마주 보이는 복강막에 같은 크기로 손상을 가하였다. 두 손상면이 맞닿도록 마찰 손상 부위로부터 약 1cm 떨어진 3곳을 봉합사로 고정함으로써 조직의 유착을 유도하였다. 여기에 각각의 시험물질을 주입하였다. 시험종료일까지 생존한 동물에 대하여 CO2 가스 흡입법을 사용하여 안락사 시킨 후 부검하여 육안적 병리검사를 실시하고 개체별로 유착정도, 유착세기 및 유착면적을 기록하였다. 유착부위 조직은 조직학적 검사를 위해 10% 중성 포르말린에 고정하였다.After anesthesia, epilation was performed on the surgical site, and sterilized with povidone, and then incised 4-5 cm along the midline of the abdominal cavity. The appendix was taken out, and abrasion was made by using a bone burr with a size of 1 cm x 2 cm, and the same size of the peritoneum was damaged. Tissue adhesion was induced by fixing three places about 1 cm away from the friction damage site with sutures so that the two damaged surfaces abut. Each test substance was injected here. Animals that survived until the end of the test were euthanized using CO 2 gas inhalation, and then autopsied to perform a gross pathological examination, and the degree of adhesion, adhesion strength, and adhesion area were recorded for each individual. The adherent tissue was fixed in 10% neutral formalin for histological examination.
이때, 유착방지효과의 측정기준은 아래 표 10 내지 11에 나타내었다.At this time, the measurement criteria of the adhesion prevention effect is shown in Tables 10 to 11 below.
<표 10> 유착면의 유착 정도에 따른 분류<Table 10> Classification by adhesion degree of adhesion surface
<표 11> 유착면 분리시 떨어지는 세기에 의한 분류<Table 11> Classification by falling strength when separating adhesion surfaces
<표 12>Table 12
상기 표 12에 나타낸 것처럼, 본 발명의 실시예 6 내지 7 및 실시예 10 내지 11을 통해 제조된 하이드로겔 조성물은 유착방지 효과가 우수한 것을 알 수 있다.As shown in Table 12, it can be seen that the hydrogel compositions prepared through Examples 6 to 7 and Examples 10 to 11 of the present invention have excellent anti-adhesion effects.
육안소견 관찰에 의한 유착의 평가는 Vlahos 등 (Vlahos A, Yu P, Lucas CE, Ledgerwood AM. Effect of a composite membrane of chitosan and Poloxamer gel on post operative adhesive interactions, The American Surgeon 2001, 67:15-21)의 방법에 따라 실시하였다. 구체적으로, 유착면의 유착 정도에 따른 분류 (0 ~ 5, 표 10), 손으로 유착면을 분리시켰을 때 두 면이 떨어지는 세기에 의한 분류(1 ~ 4, 표 11) 및 유착 부위의 면적을 측정하여 유착 정도를 평가하고, 그 결과를 표 12에 나타내었다.Evaluation of adhesion by visual observation was performed by Vlahos et al. (Vlahos A, Yu P, Lucas CE, Ledgerwood AM.Effect of a composite membrane of chitosan and Poloxamer gel on post operative adhesive interactions, The American Surgeon 2001, 67: 15-21 ). Specifically, classification according to the degree of adhesion of the adhesion surface (0 ~ 5, Table 10), classification by the strength that the two surfaces fall when separating the adhesion surface by hand (1 ~ 4, Table 11) and the area of the adhesion site The degree of adhesion was evaluated by measurement, and the results are shown in Table 12.
<실험예 3> 복합하이드로겔의 유착방지 효능 및 약물방출효과 동물 실험 <Experimental Example 3> Effect of anti-adhesion and drug release effect of composite hydrogels Animal Experiment
상기 실시예 17 내지 32에서 제조된 복합하이드로겔을 사용하였다.The composite hydrogels prepared in Examples 17 to 32 were used.
실험 진행은 마우스 입고 후 일주일간 안정화하였다. MKN74 위암 위세포주를 subcutaneous injection 진행하였다. 종양의 크기가 평균 100㎣이 되었을 때 그룹을 나눈 후 약물 복합하이드로겔 투여를 진행하였다. 100㎣ 크기에서부터 3일 간격으로 tumor의 크기를 측정하고 마우스의 중량을 측정하였다. 복합하이드로겔 주입 후 마우스에 이상이 없는 지 확인하였고, 복합하이드로겔 주입 종료 후 종양을 적출한 후 종양 무게를 측정하였다. 그리고 적출된 부위 장기의 유착 유무를 확인하였다. 실험재료는 마우스 6마리를 사용하여 진행하였다. 실험실 온도는 22±2℃, 상대습도는 0±10%, 사료는 Purina 실험동물용 쥐 사료를 사용하였으며, 음수는 모두 R/O수를 공급하며 연 2회 수질검사를 시행하였다. 미생물 검사는 sentinel animal을 이용하여 자체적으로 시행하였다. 실험 동물의 종 및 계통은 마우스, Balb/c nude, SPF이다. 중앙실험동물 SLC(일본)에서 구입하였으며 5주령된 암컷을 사용하였다. 실험에 사용한 세포주는 MKN74(위암세포주, 한국 세포주은행)이며, RPM1640(Welgene)+10% FBS(ATCC) 의 배양조건에서 배양하였다.The experiment progress was stabilized for one week after wearing the mouse. MKN74 gastric cancer gastric cell line was subjected to subcutaneous injection. When the tumor size was on average 100㎣, the group was divided and then the drug complex hydrogel was administered. Tumors were sized at 100-mm size every 3 days and the weight of the mice was measured. After the injection of the complex hydrogel, it was confirmed that there was no abnormality in the mouse, and after the injection of the complex hydrogel, tumors were extracted and tumor weight was measured. In addition, the presence or absence of adhesion of the extracted organs was confirmed. Experimental material was conducted using 6 mice. The laboratory temperature was 22 ± 2 ℃, the relative humidity was 0 ± 10%, the feed was used as a rat feed for Purina laboratory animals, and negative water was supplied with R / O water and water quality tests were conducted twice a year. Microbiological testing was conducted by itself using sentinel animals. The species and lineage of experimental animals are mice, Balb / c nude, SPF. It was purchased from the central laboratory animal SLC (Japan) and a 5 week old female was used. The cell line used in the experiment was MKN74 (stomach cancer cell line, Korea Cell Line Bank), and cultured under the culture conditions of RPM1640 (Welgene) + 10% FBS (ATCC).
아래 도 내지 3에 나타낸 것처럼, 6일까지는 그룹간의 큰 차이가 나타나지 않았다. 그러나 9일부터 PBS처리 군과 항암제가 포함된 복합하이드로겔 처리 군 간의 종양 크기에서 차이가 나타나는 것을 알 수 있다.As shown in Figs. 3 to 3, there was no significant difference between groups until day 6. However, from day 9, it can be seen that there is a difference in tumor size between the PBS-treated group and the complex hydrogel-treated group containing the anticancer agent.
최종 30일에 확인 결과 PBS처리군 대비 복합하이드로겔의 종양크기가 30%감소함을 보였다.As a result of confirmation on the last 30 days, the tumor size of the complex hydrogel was reduced by 30% compared to the PBS treatment group.
또한, 도 5 내지 8에 나타낸 것처럼, PBS처리군에서는 장 유착이 발생하였지만, 본 발명에 따른 하이드로겔 조성물의 처리군에서는 유착이 발생되지 않은 것을 알 수 있다.In addition, as shown in Figs. 5 to 8, intestinal adhesions occurred in the PBS treatment group, but it can be seen that adhesions did not occur in the treatment group of the hydrogel composition according to the present invention.
결과적으로 도2 내지 8에 나타낸 것처럼, Vehicle(PBS) 처리 군과 비교하였을 때 항암제가 포함된 처리 군에서 종양크기가 30% 감소하였다. 또한 30일 이후 장기 내부의 유착은 발생하지 않은 것을 알 수 있다.As a result, as shown in Figures 2 to 8, compared to the Vehicle (PBS) treatment group, the tumor size was reduced by 30% in the treatment group containing the anticancer agent. In addition, it can be seen that after 30 days, internal adhesions did not occur.
파클리탁셀 및 케파시타빈가 함유된 하이드로겔 조성물에서도 상기와 유사한 결과를 나타내었다.Similar results were also observed in the hydrogel composition containing paclitaxel and kefacitabine.
<실험예 4> 복합하이드로겔 제조과정 중 생분해성 입자의 제조<Experimental Example 4> Preparation of biodegradable particles during the complex hydrogel manufacturing process
상기 실시예 113에서 제조한 입자를 입경분석기로 측정하였다. 또한 10배율의 마이크로 현미경으로 입자의 상태를 관측하였다.The particles prepared in Example 113 were measured with a particle size analyzer. In addition, the state of the particles was observed by a microscopic microscope at 10 times magnification.
도 9 내지 10에 나타낸 것처럼, 입자는 구형으로 제조되었으며 평균 입자 크기는 10 내지 100마이크로를 나타내었다.9 to 10, the particles were manufactured in a spherical shape, and the average particle size was 10 to 100 microns.
그러나 삼원 공중합체의 함량이 높아질수록 입자의 크기는 감소하고, 생분해성 고분자의 함량이 높아짐에 따라 입자의 크기가 증가함을 알 수 있다.However, it can be seen that as the content of the ternary copolymer increases, the particle size decreases, and as the content of the biodegradable polymer increases, the particle size increases.
따라서, 본 발명에 따른 조직유착 방지용 하이드로겔 조성물 및 그 제조방법은 조직유착 억제성능을 갖는 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체를 기본 구조체로 하고, 수불용성 히알루론산, 소듐알지네이트를 블랜딩하여 체내 상처 부위에 고르게 도포되는 조직유착 방지용 하이드로겔 조성물을 제공한다.Therefore, the hydrogel composition for preventing tissue adhesion according to the present invention and a method for manufacturing the same are based on a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer having tissue adhesion inhibiting performance, and blending water-insoluble hyaluronic acid and sodium alginate. By providing a hydrogel composition for preventing tissue adhesion evenly applied to the wound area in the body.
또한, 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체의 녹는점 및 고분자상호간의 반발력을 이용하여 난용성 항암제를 안정적으로 방출하는 조직유착 방지용 하이드로겔 조성물을 제공한다.In addition, it provides a hydrogel composition for preventing tissue adhesion stably releasing poorly soluble anti-cancer agents by using the melting point of the polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer and the repulsive force between polymers.
또한, 생분해성 고분자가 함유되어 우수한 생분해성을 나타내는 조직유착 방지용 하이드로겔 조성물을 제공한다.In addition, it provides a hydrogel composition for preventing tissue adhesion, which exhibits excellent biodegradability by containing a biodegradable polymer.
Claims (11)
상기 수불용성 히알루론산은 에탄올 수용액 95 내지 99 중량%에 분자량이 500 내지 3000kDa인 히알루론산 1 내지 5 중량%를 혼합하여 혼합물을 제조하고, 상기 혼합물에 함유된 히알루론산 100 중량부 대비 및 가교제 0.02 내지 0.1 중량부를 더 혼합하여 제조되는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물.
Polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer 15 to 30% by weight, water-insoluble hyaluronic acid 2.5 to 4.5% by weight, sodium alginate 0.1 to 1% by weight and purified water remaining,
The water-insoluble hyaluronic acid is prepared by mixing 1 to 5% by weight of hyaluronic acid having a molecular weight of 500 to 3000kDa in 95 to 99% by weight of an ethanol aqueous solution, compared to 100 parts by weight of hyaluronic acid contained in the mixture and 0.02 to crosslinking agent Hydrogel composition for preventing tissue adhesion, characterized in that it is prepared by further mixing 0.1 parts by weight.
상기 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체는 분자량이 1 내지 500kDa인 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물.
The method according to claim 1,
The polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer is a hydrogel composition for preventing tissue adhesion, characterized in that the molecular weight is 1 to 500kDa.
상기 에탄올 수용액은 pH가 9.5 내지 13이고, 질량농도가 70 내지 80%인 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물.
The method according to claim 1,
The ethanol aqueous solution has a pH of 9.5 to 13, a hydrogel composition for preventing tissue adhesion, characterized in that the mass concentration is 70 to 80%.
상기 가교제는 1,4-부탄디올디글리시딜에테르로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물.
The method according to claim 1,
The cross-linking agent is a hydrogel composition for preventing tissue adhesion, characterized in that consisting of 1,4-butanediol diglycidyl ether.
상기 조직유착 방지용 하이드로겔 조성물에는 상기 조직유착 방지용 하이드로겔 조성물 100 중량부 대비 난용성 항암제 0.1 내지 10 중량부가 더 함유되며,
상기 난용성 항암제는 도세탁셀, 도세탁셀 수화물, 파클리탁셀, 파클리탁셀 수화물, 카페시타빈 및 카페시타빈 수화물로 이루어진 그룹에서 선택된 하나로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물.
The method according to claim 1,
The hydrogel composition for preventing tissue adhesion further contains 0.1 to 10 parts by weight of a poorly soluble anti-cancer agent compared to 100 parts by weight of the hydrogel composition for preventing tissue adhesion,
The sparingly soluble anti-cancer agent is a docetaxel, docetaxel hydrate, paclitaxel, paclitaxel hydrate, capecitabine, and a hydrogel composition for preventing tissue adhesion, characterized in that consisting of one selected from the group consisting of capecitabine hydrate.
상기 조직유착 방지용 하이드로겔 조성물에는 상기 조직유착 방지용 하이드로겔 조성물에 함유된 폴리에틸렌옥사이드-폴리프로필렌옥사이드-폴리에틸렌옥사이드 삼원 공중합체 100 중량부 대비 생분해성 고분자 10 내지 50 중량부가 더 함유되며,
상기 생분해성 고분자는 PLLA(Poly-L-lactic-Acid), PLGA(poly-lactic-co -glycolic acid), PDO(Polydioxanone) 및 PCL(polycaprolactone)으로 이루어진 그룹에서 선택된 하나로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물.
The method according to claim 1,
The hydrogel composition for preventing tissue adhesion further contains 10 to 50 parts by weight of a biodegradable polymer compared to 100 parts by weight of a polyethylene oxide-polypropylene oxide-polyethylene oxide ternary copolymer contained in the hydrogel composition for preventing tissue adhesion,
The biodegradable polymer is a tissue adhesion characterized by consisting of one selected from the group consisting of poly-L-lactic-Acid (PLLA), poly-lactic-co-glycolic acid (PLGA), polydioxanone (PDO) and polycaprolactone (PCL) Prevention hydrogel composition.
상기 공중합체용해단계를 통해 제조된 용해물에 수불용성 히알루론산을 혼합하고, 10 내지 20℃의 온도로 교반하는 히알루론산혼합단계; 및
상기 히알루론산혼합단계를 통해 제조된 혼합물에 소듐알지네이트를 혼합하고 5 내지 20℃의 온도로 교반하는 소듐알지네이트혼합단계;로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물의 제조방법.
A copolymer dissolving step in which a polyethylene oxide-polypropylene oxide-polyethylene oxide terpolymer having a molecular weight of 1 to 500 kDa is dissolved by heating at a temperature of 60 to 100 ° C. for 1 to 2 hours;
A hyaluronic acid mixing step of mixing water-insoluble hyaluronic acid in the melt prepared through the copolymer dissolving step and stirring at a temperature of 10 to 20 ° C; And
A method of preparing a hydrogel composition for preventing tissue adhesion, comprising: mixing sodium alginate with a mixture prepared through the hyaluronic acid mixing step and stirring at a temperature of 5 to 20 ° C.
상기 공중합체용해단계와 상기 히알루론산혼합단계 사이에는 상기 공중합체용해단계를 통해 제조된 용해물에 난용성 항암제를 혼합하는 난용성항암제혼합단계가 더 진행되며,
상기 난용성 항암제는 도세탁셀, 도세탁셀 수화물, 파클리탁셀, 파클리탁셀 수화물, 카페시타빈 및 카페시타빈 수화물로 이루어진 그룹에서 선택된 하나로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물의 제조방법.
The method according to claim 9,
Between the copolymer dissolving step and the hyaluronic acid mixing step, a poorly soluble anticancer agent mixing step of mixing a poorly soluble anticancer agent into the lysate prepared through the copolymer dissolving step further proceeds
The poorly soluble anti-cancer agent is a docetaxel, docetaxel hydrate, paclitaxel, paclitaxel hydrate, capecitabine and a method for producing a hydrogel composition for preventing tissue adhesion, characterized in that consisting of one selected from the group consisting of capecitabine hydrate.
상기 공중합체용해단계와 상기 히알루론산혼합단계 사이에는 상기 공중합체용해단계를 통해 제조된 용해물에 생분해성 고분자를 혼합하는 생분해성고분자혼합단계가 더 진행되며,
상기 생분해성 고분자는 PLLA(Poly-L-lactic-Acid), PLGA(poly-lactic-co -glycolic acid), PDO(Polydioxanone) 및 PCL(polycaprolactone)으로 이루어진 그룹에서 선택된 하나로 이루어지는 것을 특징으로 하는 조직유착 방지용 하이드로겔 조성물의 제조방법.The method according to claim 9,
Between the copolymer dissolving step and the hyaluronic acid mixing step, a biodegradable polymer mixing step in which a biodegradable polymer is mixed with a lysate prepared through the copolymer dissolving step further proceeds,
The biodegradable polymer is a tissue adhesion characterized by consisting of one selected from the group consisting of poly-L-lactic-Acid (PLLA), poly-lactic-co-glycolic acid (PLGA), polydioxanone (PDO) and polycaprolactone (PCL) Method for preparing a hydrogel composition for prevention.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202080067505.3A CN114514043A (en) | 2019-07-08 | 2020-08-31 | Temperature-sensitive hydrogel composition for preventing tissue adhesion and preparation method thereof |
| PCT/KR2020/011633 WO2021040493A1 (en) | 2019-07-08 | 2020-08-31 | Temperature-sensitive hydrogel composition for preventing tissue adhesion, and preparation method therefor |
| JP2022513910A JP2022546512A (en) | 2019-07-08 | 2020-08-31 | Hydrogel composition for temperature-sensitive tissue adhesion prevention and method for producing the same |
| US17/638,821 US20220280700A1 (en) | 2019-07-08 | 2020-08-31 | Temperature-Sensitive Hydrogel Composition for Preventing Tissue Adhesion, and Preparation Method Therefor |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020190082343 | 2019-07-08 | ||
| KR20190082343 | 2019-07-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR102093660B1 true KR102093660B1 (en) | 2020-03-26 |
Family
ID=69958859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020190107356A KR102093660B1 (en) | 2019-07-08 | 2019-08-30 | Temperature-sensitive tissue adhesion prevention hydrogel composition and its manufacturing method |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20220280700A1 (en) |
| JP (1) | JP2022546512A (en) |
| KR (1) | KR102093660B1 (en) |
| CN (1) | CN114514043A (en) |
| WO (1) | WO2021040493A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021040493A1 (en) * | 2019-07-08 | 2021-03-04 | (주)리젠바이오참 | Temperature-sensitive hydrogel composition for preventing tissue adhesion, and preparation method therefor |
| CN114652904A (en) * | 2022-03-17 | 2022-06-24 | 天津大学 | Anticoagulant zwitterionic hydrogel coating and preparation method thereof |
| WO2023163289A1 (en) * | 2022-02-23 | 2023-08-31 | 주식회사 지씨에스 | Hydrogel composition capable of minimally invasive implantation based on polydisperse peptides having different structures and uses thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100431491B1 (en) * | 1999-07-20 | 2004-05-14 | 주식회사 삼양사 | Biodegradable poly(alkylene oxide)-poly(p-dioxanone)block copolymer soluble in organic solvents, and drug delivery composition comprising same |
| JP2006333942A (en) * | 2005-05-31 | 2006-12-14 | National Cardiovascular Center | Postsurgical adhesion prevention agent |
| US20090324720A1 (en) * | 2008-04-22 | 2009-12-31 | Angiotech Pharmaceuticals, Inc. | Biocompatible crosslinked hydrogels, drug-loaded hydrogels and methods of using the same |
| JP2013198737A (en) * | 2012-03-26 | 2013-10-03 | Genewel Co Ltd | Implantation material using biocompatible polymer |
| KR101871930B1 (en) * | 2016-07-15 | 2018-07-02 | 한국교통대학교산학협력단 | Thermo-sensitive Anti-adhesion Hydrogel Using Hyaluronic Acid Derivative And Manufacturing Method Thereof |
| KR20180075601A (en) * | 2015-10-28 | 2018-07-04 | 테크놀로지 이노베이션 모멘텀 펀드 (이스라엘) 리미티드 파트너쉽 | Composite bioadhesive sealant |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8940311B2 (en) * | 2004-10-21 | 2015-01-27 | Tae-Hong Lim | In situ controlled release drug delivery system |
| KR100849185B1 (en) * | 2006-01-19 | 2008-07-30 | 서울산업대학교 산학협력단 | Chitosan or Hyaluronic acid-Polyethylene oxide- and Chitosan-Hyaluronic acid-Polyethylene oxide-Based hydrogel and Manufacturing Method Therefor |
| CN101229150A (en) * | 2007-11-22 | 2008-07-30 | 山东蓝金生物工程有限公司 | Thermostatic sustained release injection containing taxane and preparing method thereof |
| CN102068719A (en) * | 2011-01-18 | 2011-05-25 | 复旦大学 | Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof |
| CN103007338B (en) * | 2011-09-28 | 2014-10-22 | 韩冰 | Application of gel material for dental cavity filling material after tooth extraction |
| CN106659823B (en) * | 2014-07-24 | 2019-11-12 | 玫帝托克斯股份有限公司 | Thermo-responsive is anti-sticking to be used in conjunction composition and application thereof |
| CN104645425B (en) * | 2015-03-20 | 2017-08-11 | 成都市南丁医用材料有限公司 | Anti- Asherman's syndrom material |
| US11197948B2 (en) * | 2017-01-31 | 2021-12-14 | University Of The Witwatersrand, Johannesburg | Thermoresponsive hydrogel |
| KR102093660B1 (en) * | 2019-07-08 | 2020-03-26 | (주)리젠바이오참 | Temperature-sensitive tissue adhesion prevention hydrogel composition and its manufacturing method |
-
2019
- 2019-08-30 KR KR1020190107356A patent/KR102093660B1/en active IP Right Grant
-
2020
- 2020-08-31 CN CN202080067505.3A patent/CN114514043A/en active Pending
- 2020-08-31 JP JP2022513910A patent/JP2022546512A/en active Pending
- 2020-08-31 WO PCT/KR2020/011633 patent/WO2021040493A1/en active Application Filing
- 2020-08-31 US US17/638,821 patent/US20220280700A1/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100431491B1 (en) * | 1999-07-20 | 2004-05-14 | 주식회사 삼양사 | Biodegradable poly(alkylene oxide)-poly(p-dioxanone)block copolymer soluble in organic solvents, and drug delivery composition comprising same |
| JP2006333942A (en) * | 2005-05-31 | 2006-12-14 | National Cardiovascular Center | Postsurgical adhesion prevention agent |
| US20090324720A1 (en) * | 2008-04-22 | 2009-12-31 | Angiotech Pharmaceuticals, Inc. | Biocompatible crosslinked hydrogels, drug-loaded hydrogels and methods of using the same |
| JP2013198737A (en) * | 2012-03-26 | 2013-10-03 | Genewel Co Ltd | Implantation material using biocompatible polymer |
| KR20180075601A (en) * | 2015-10-28 | 2018-07-04 | 테크놀로지 이노베이션 모멘텀 펀드 (이스라엘) 리미티드 파트너쉽 | Composite bioadhesive sealant |
| KR101871930B1 (en) * | 2016-07-15 | 2018-07-02 | 한국교통대학교산학협력단 | Thermo-sensitive Anti-adhesion Hydrogel Using Hyaluronic Acid Derivative And Manufacturing Method Thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021040493A1 (en) * | 2019-07-08 | 2021-03-04 | (주)리젠바이오참 | Temperature-sensitive hydrogel composition for preventing tissue adhesion, and preparation method therefor |
| WO2023163289A1 (en) * | 2022-02-23 | 2023-08-31 | 주식회사 지씨에스 | Hydrogel composition capable of minimally invasive implantation based on polydisperse peptides having different structures and uses thereof |
| CN114652904A (en) * | 2022-03-17 | 2022-06-24 | 天津大学 | Anticoagulant zwitterionic hydrogel coating and preparation method thereof |
| CN114652904B (en) * | 2022-03-17 | 2023-07-07 | 天津大学 | Amphoteric ion hydrogel coating for anticoagulation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US20220280700A1 (en) | 2022-09-08 |
| WO2021040493A1 (en) | 2021-03-04 |
| JP2022546512A (en) | 2022-11-04 |
| CN114514043A (en) | 2022-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liang et al. | Implantable and degradable antioxidant poly (ε-caprolactone)-lignin nanofiber membrane for effective osteoarthritis treatment | |
| EP3449956B1 (en) | Medical hydrogel composition, and medical hydrogel, preparation method therefor and application thereof | |
| US6869938B1 (en) | Compositions of polyacids and polyethers and methods for their use in reducing adhesions | |
| KR102093660B1 (en) | Temperature-sensitive tissue adhesion prevention hydrogel composition and its manufacturing method | |
| Bang et al. | Preventing postoperative tissue adhesion using injectable carboxymethyl cellulose-pullulan hydrogels | |
| EP2821087B1 (en) | Anti-adhesion polymer composition capable of supporting growth factor | |
| US20050074495A1 (en) | Compositions of polyacids and methods for their use in reducing adhesions | |
| US10864302B2 (en) | Adhesion prevention agent comprising injectable thermosensitive wood based-oxidized cellulose nanofiber | |
| AU778853B2 (en) | Compositions of polyacids and polyethers and methods for their use in reducing adhesions | |
| EP2932989B1 (en) | Tissue sealant in which collagen and fibrin are mixed, and method for preparing same | |
| EP3027659B1 (en) | Low swell tissue adhesive and sealant formulations | |
| US20230220190A1 (en) | Anti-adhesion polymer composition | |
| Liu et al. | Sutureless transplantation using a semi-interpenetrating polymer network bioadhesive for ocular surface reconstruction | |
| Jeong et al. | Development of novel biocompatible thermosensitive anti-adhesive agents using human-derived acellular dermal matrix | |
| KR101668349B1 (en) | Adhesion barrier agent | |
| Tint et al. | An in vitro assessment of the thermoreversible PLGA‐PEG‐PLGA copolymer: Implications for Descemet's membrane endothelial keratoplasty | |
| KR20020012170A (en) | Compositions of polyacids and polyethers and methods for their use in reducing adhesions | |
| KR20190085249A (en) | Compositions for the prevention of tissue adhesion comprising a hyaluronic acid-gelatin polymer | |
| CN117736465A (en) | Injectable Hemoadhican polysaccharide hydrogel, preparation method and application thereof | |
| Pires Moedas De Almeida Barros et al. | Photocurable GelMA adhesives for corneal perforations | |
| CN114728099A (en) | Tissue repair compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |